Studies performed over the past 10 years have documented that the interaction of the T cell receptor (TCR) with its specific ligand, peptide-MHC, is only one component of the cascade of events required for the activation of antigen-specific T cells. The primary goals of our studies are to characterize other cell surface antigens (co-receptors) and their soluble or cell-associated ligands (counter-receptors) which play critical roles in cell-cell interaction and the interaction of T cells with their environment (for example, extracellular matrix (ECM)-proteins). We have focused our efforts in two specific areas: 1) We have characterized a prominent subpopulation of GammaDelta T cells which express the CGamma4, VDelta6 TCR and which appears to recognize an autoantigen expressed on the surface of the activated T cells themselves. However, engagement of this TCR by itself is not sufficient to induce T cell activation as this subpopulation requires the co-receptor function of the vitronectin receptor (VNR) which binds to the RGDS sequence in ECM-proteins. We have produced two soluble forms of the CGamma4, VDelta6 TCR and these novel reagents should allow us to characterize the stimulatory autoantigen and/or the restriction element which regulates activation of this subpopulation of T cells. 2) We have demonstrated that the very early activation (VEA) antigen which has been defined by monoclonal antibody (mAb) H1.2F3 functions as a cell surface receptor for costimulatory signals derived from accessory cells. Non-stimulatory F(ab')2 fragments of H1.2F3 block all accessory dependent T cell function, but have no effects on accessory cell independent T cell activation. Furthermore, when populations of T cells primed in vivo to two antigens are stimulated in culture by accessory cells and one antigen in the presence of the F(ab')2 reagent, they cannot be restimulated by the antigen used in the first culture, but mount a normal response to a second antigen. This result suggest that the failure to engage the VEA may result in the induction of clonal anergy. An increase in our understanding of the function of these co-receptors, further characterization of their ligands or counter-receptors, and the availability of unique reagents (mAbs, soluble receptors) should offer us the opportunity to manipulate and regulate ongoing immune responses in vivo.